The present invention relates to a process for producing an optically active 3-hydroxy-4-methoxypyrrolidine, which is a synthesis intermediate of a quinuclidine derivative useful, as a squalene synthetase inhibitor, for prevention and treatment of hyperlipemia such as arteriosclerotic disease, ischemic heart disease and the like.
At present, an HMG-CoA reductase inhibitor is widely used as a cholesterol-decreasing agent. Since this inhibitor produces an effect on metabolic materials other than cholesterol, a side effect thereof is becoming a problem. A squalene synthetase functions in the lower course than an HMG-CoA reductase and an isoprene synthesis system in the biosynthesis system of cholesterol. Therefore, it is expected that the squalene synthetase overcomes the side effect problem of the HMG-CoA reductase inhibitor. However, no squalene synthetase inhibitor which produces only a small side effect and exhibits sufficient efficacy as hyperlipemia therapeutic agent has been created before.
After eager researches, the present inventors found that a quinuclidine derivative comprising 3-hydroxy-4-methoxypyrrolidine or the like has a superior squalene synthetase inhibiting effect and is useful as a hyperlipemia therapeutic agent. The inventors then filed a Patent Application about the quinuclidine derivative (WO 01/23383).
In a process for producing a quinuclidine derivative comprising 3-hydroxy-4-methoxypyrrolidine or the like, described in this Patent Application (WO 01/23383), 3-hydroxy-4-methoxypyrrolidine, which is concerned with the present invention, is not used as an intermediate. Therefore, this process is unsatisfactory as an industrial process for producing the quinuclidine derivative in light of a large number of the steps included in the process and the yield thereof as a whole. 3-Hydroxy-4-methoxypyrrolidine is new as a racemic body or an optically active substance, and has not been known so far.
An object of the present invention is to provide a useful process for producing optically active 3-hydroxy-4-methoxypyrrolidine, which is an intermediate for producing the above-mentioned quinuclidine derivative.
In the present invention, 3-hydroxy-4-methoxypyrrolidine is used. Therefore, the number of steps in the method of the present invention can be smaller than that of the above-mentioned process (WO 01/23383). Accordingly, the present invention can be used to produce the quinuclidine derivative effectively and industrially.
The inventors have found out a useful process for producing optically active 3-hydroxy-4-methoxypyrrolidine, that is, the following inventions  less than 1 greater than  to  less than 11 greater than :
 less than 1 greater than  A process for producing optically active 3-hydroxy-4-methocypyrrolidine represented by the following formula (1-7): 
xe2x80x83wherein R1a and R1b are different from each other, and each of R1a and R1b represents a hydrogen atom or a hydroxyl group, and R2a and R2b are different from each other, and each of R2a and R2b represents a hydrogen atom or a methoxy group], a salt thereof or a hydrate thereof, comprising the steps of:
subjecting a pyrrolidine derivative represented by the following formula (1-4): 
xe2x80x83wherein R1a, R1b, R2a and R2b have the same definition as mentioned above, and R3a and R3b are different 1 mm each other, and each of R3a and R3b represents a hydrogen atom or a methyl group, to optical division purification by using an optically active dibenzoyltartaric acid derivative represented by the following formula (1-5): 
xe2x80x83wherein R6a, R6b, R6c and R6d each independently represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or a C1-6 alkyl group, and R4 and R5 are different tram each other, and each of R4 end R5 represents a hydrogen atom or a carboxyl group, to yield a compound (1-6) represented by the following formula (1-6): 
xe2x80x83wherein R1a, R1b, R2a, R2b, R3a and R3b have the same definition as mentioned above; and
removing the 1-phenylethyl group of the compound (1-6), to yield the 3-hydroxy-4-methoxypyrrolidine, the salt thereof or the hydrate thereof;
 less than 2 greater than  A process for producing optically active 3-hydroxy-4-methoxypyrrolidine represented by the following formula (1-7): 
xe2x80x83wherein R1a and R1b are different from each other, and each of R1a and R1b represents a hydrogen atom or a hydroxyl group and R2a and R2b are different from each other, and each of R2a and R2b represents a hydrogen atom or a methoxy group, a salt thereof or a hydrate thereof, comprising the steps of:
reacting an oxysilafle derivative represented by the following formula (1-1) 
xe2x80x83wherein L1 represents a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, with an amine derivative represented by the following formula (1-2) 
xe2x80x83wherein R3a and R3b are different from each other, and each of R3a and R3b represents a hydrogen atom or a methyl group, to yield a pyrrolidine derivative (1-3) represented by the following formula (1-3): 
xe2x80x83wherein R3a and R3b have the same definition as mentioned above;
reacting the derivative (1-3) with a methoxylating agent, to yield a pyrrolidine derivative (1-4): 
xe2x80x83wherein R1a, R1b, R2a, R2b, R3a and R3b have the same definition as mentioned above;
subjecting the derivative (1-4) to optical division purification by using an optically active dibenzoyltartaric acid derivative represented by the following formula (1-5): 
xe2x80x83wherein R6a, R6b, R6c and R6d each independently represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or a C1-6 alkyl group, and R4 and R5 are different from each other, and each of R4 and R5 represents a hydrogen atom or a carboxyl group, to yield a compound (1-6) represented by the following formula (1-6): 
xe2x80x83wherein R1a, R1b, R2a, R2b, R3a and R3b have the same definition as mentioned above; and
removing the 1-phenylethyl group of the compound (1-8), to yield the 3-hydroxy-4-methoxypyrrolidine, the salt thereof or the hydrate thereof;
 less than 3 greater than  The method according to the above-mentioned item  less than 1 greater than  or  less than 2 greater than , wherein each of R1a and R2b represents a hydrogen atom;
 less than 4 greater than  The method according to the above-mentioned item  less than 1 greater than  or  less than 2 greater than , wherein each of R1b and R2a represents a hydrogen atom;
 less than 5 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 4 greater than , wherein R3a represents a methyl group;
 less than 6 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 4 greater than , wherein R3b represents a methyl group;
 less than 7 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 6 greater than , wherein said compound (1-4) represents a mixture of compounds represented by the following formulae (1-4a) and (1-4b) (wherein R3a and R3b are different from each other, and each of R3a and R3b represents hydrogen atom or a methyl group), in which the mixture having a given mixture ratio of compound (1-4a) to (1-4b): 
 less than 8 greater than  The method according to the above-mentioned item  less than 7 greater than , wherein said compound (1-4) is said mixture of said compounds (1-4a) and (1-4b) having a ratio of 1:1 of said compounds (1-4a) to (1-4b);
 less than 9 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 8 greater than . wherein R4 represents a hydrogen atom;
 less than 10 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 8 greater than , wherein R5 represents a hydrogen atom; and
 less than 11 greater than  The method according to any one of the above-mentioned items  less than 1 greater than  to  less than 10 greater than , wherein each of R6a, R6b, R6c and R6d represents a hydrogen atom.
The present invention will be described in detail hereinafter.
First, meanings of terms, symbols and the like described hereinafter will be defined.
In the present specification and claims, a structural formula of a compound may conveniently represent a given isomer. Compounds of the present invention may be isomers thereof such as all geometrical isomers generated from the structure of the compounds, optical isomers based on an asymmetric carbon thereof, stereoisomers and enantiomers, and mixtures of some of the isomers. Accordingly, the compounds of the present invention are not limited to those defined by the structural formula thereof, and may be any one of the isomers, or a mixture of some of the isomers. Some compounds of the present invention may have an asymmetric carbon in the molecule thereof, and thus may be optically active substances thereof or racemic bodies thereof. The compounds of the present invention may have crystal polymorphisms, but are not limited to the crystal form thereof. The compounds of the present invention may be in a single crystal form or in a mixed crystal form. Furthermore, the compounds of the present invention may be in a dehydrate form or in a hydrate form.
In the present specification and claims, the term xe2x80x9cC1-6 alkyl groupxe2x80x9d means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, 1-methylpropyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, and 3-methylpentyl groups.
In the present specification and claims, the term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine or iodine atom.
In the present specification and claims, the term xe2x80x9cC1-6 alkoxy groupxe2x80x9d means an oxy group to which the above-defined xe2x80x9cC1-6 alkyl groupxe2x80x9d is bonded. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy, neopentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, n-hexyloxy, i-hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy groups.
The methoxylating agent means a sodium methoxide, potassium methoxide, magnesium methoxide or the like, or a solution thereof. The solvent of the solution may be an organic solvent such as methanol.
The optically active dibenzoyltartaric acid derivative (1-5) is an optically active compound (1-5) represented by the following formula: 
wherein R6a, R6b, R6c and R6d each independently represents a hydrogen atom, a halogen atom, a C1-6 alkoxy group or a C1-6 alkyl group, R4 and R5 are different from each other, and each of R4 and R5 represents a hydrogen atom or a carboxyl group; a salt thereof, or salts thereof. The present compound (1-5) is preferably a hydrate of D-dibenzoyltartaric acid or L-dibenzoyltartaric acid, and is more preferably a monohydrate of D-dibenzoyltartaric acid.
Specific examples of the compound (1-6) may include compounds represented by the following formula: 
Preferred specific examples may be compounds represented by the following formula: 
A more preferred specific example may be a compound represented by the following formula: 
Specific examples of the compound (1-7) may include compounds represented by the following formula: 
Preferred specific examples may be compounds represented by the following formula: 
A more preferred specific example may be a compound represented by the following formula: 
The salt referred to in the present invention may include, but is not limited to, inorganic salts such as hydrofluorides, hydrochlorides, sulfates, nitrates, perchlorates, phosphates, carbonates, bicarbonates, hydrobromates, hydroiodides and the like; salts of organic carboxylic acids such as acetates, maleates, fumarates, oxalates, lactates, tartrates, trifluoroacetates and the like; organic sulfonates such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, hydroxymethanesulfonates, hydroxyethanesulfoantes, benzenesulfonates, toluenesulfonates, taurine salts and the like; amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, N-methylglucamine salts, diethanolamine salts, triethanolamine salts, tris(hydroxymethylamino)methane salts, phenetylbenzylamine salts and the like; alkali metal salts such as sodium salts, potassium salts and the like; alkali earth metal salts such as magnesium salts, calcium salts and the like; and amino acid salts such as arginine salts, lysine salts, serine salts, glycine salts, aspartate salts, glutamate salts and the like. Preferably, pharmaceutically acceptable salts are used.
The compound of the present invention represented by the following general formula can be synthesized by a conventionally known organic chemistry reaction and the like: 
For example, the compound can be synthesized by the following process: Synthesis method: 
wherein L1, R1a, R1b, R2a, R2b, R3a, R3b, R4, R5, R6a, R6b, R6c and R6d have the same definition as mentioned above.
A benzylamine derivative (1-2) can be reacted with a compound (1-1), to obtain a compound (1-3). In the reaction, a base may be added to the reaction system. Specific examples of the base which can be used include nitrogen-containing bases such as triethylamine, N-methylmorpholine, pyridine and the like; and inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like. Examples of a solvent for the reaction include acetone, esters such as ethyl acetate, ethers such as tetrahydrofuran and t-butyl methyl ether, lower nitriles such as acetonitrile, and aprotic solvents such as dimethylformamide, dimethyl sulfoxide and toluene. Reaction temperature may be from about 0 to 80xc2x0 C., preferably from about 20 to 50xc2x0 C. Reaction time may be 10 hours or more, usually 48 hours.
Step 2 of the conversion of the compound (1-3) to a compound (1-4) is a step of subjecting the epoxide to ring-opening reaction. The compound (1-3) can be reacted with a methoxylating agent, to obtain the compound (1-4). Examples of the methoxylating agent that can be used may include alkali metal methoxides such as sodium methoxide, lithium methoxide and the like. A solvent for the reaction may be usually methanol. Tetrahydrofuran, dimethyl sulfoxide, toluene or the like may be added thereto. Reaction temperature may be usually 40xc2x0 C. or more. Reaction time may be several hours.
Step 3 is a step of yielding a compound (1-6) from the compound (1-4) by optical division purification.
Procedure 3-1
Procedure 3-1 is a procedure of forming a salt of a tartaric acid derivative and recrystallizing the salt.
The compound (1-4) is mixed with 0.5 to 2 equivalents of a compound (1-5), to form a salt (1-5b) of the compound (1-4) and the compound (1-5), followed by crystallizing the salt. The salt (1-5b) is subjected to purification based on plural recrystallization steps until the optical purity thereof comes up to a target value. Examples of a solvent for the recrystallization may include water; lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone and the like; acetate esters such as methyl acetate, ethyl acetate and the like; ethers such as tetrahydrofuran, t-butyl methyl ether and the like; aromatic compounds such as toluene and the like; and mixture thereof. Reaction temperature may be from xe2x88x9220 to 100xc2x0 C. The time for the crystallization may be from 1 hour to 2 days, preferably from 4 hours to 24 hours.
Procedure 3-2
Procedure 3-2 is a procedure of freeing the salt (1-5b) of the tartaric acid derivative formed and purified by the procedure 3-1. To the salt (1-5b) is added an aqueous solution of an alkali metal salt such as a hydroxide, carbonate or the like, or ammonium water in an equivalent amount or more, so as to free the salt and obtain a compound (1-6). Then, the compound (1-6) is extracted with an organic solvent immiscible with water, for example, an acetate ester such as ethyl acetate or isopropyl acetate, or an ether such as t-butyl methyl ether, or an aromatic compound such as toluene. Reaction temperature may be typically from 10 to 30xc2x0 C. Reaction time is within the range of several hours.
Step 4 is a reducing step. The compound (1-6) is reduced in the presence of a palladium catalyst in the atmosphere of hydrogen, to yield a compound (1-7). Specific examples of the palladium catalyst may include Pdxe2x80x94C, Pd(OH)2 and the like. A solvent that can be used for the reaction may be a solvent that does not react with hydrogen. Examples of the solvent may include alcohols such as methanol, ethanol, propanol and the like; esters such as ethyl acetate and the like; ethers such as tetrahydrofuran, t-butyl ether and the like. Reaction temperature may be from 0 to 100xc2x0 C., and reaction time may be several hours.
After the end of the above-mentioned reaction, if desired, the resultant compound can be purified by a usual method, for example, column chromatography separation using silica gel, absorbing resin or the like, or recrystallization from a suitable solvent.